IL-13 is a secreted monomeric peptide produced mainly by Th2 cells but also by mast cells and NK cells. Biological functions of IL-13 include regulation of IgE production and modulation of Th2 development. IL-13 binds to a receptor complex consisting of IL-13 receptor alpha1 (IL-13Rα1) chain and IL-4 receptor alpha (IL-4Rα) chain. IL-13 binding triggers signal transduction events mainly through STAT6. IL-13 binds with low affinity to the IL-13 Rα1 alone and does not bind to IL-4Rα1. Contrary to this, IL-4 binds to IL-4Rα alone and does not bind to IL-13Rα1 alone. Another receptor for IL-13 has been described, the IL-13Rα2. IL-13 binds with high affinity to this receptor. Likely this receptor acts as a decoy receptor.
Inducible overexpression of IL-13 in transgenic mice results in a phenotype that shares many characteristics with asthmatic patients. They show mucus metaplasia, macrophage, lymphocyte and eosinophil-rich inflammation, upregulation of proteases like MMP-9, -12, -13, -2 and -14, cathepsin B, H, K and S and they also present subepithelial fibrosis. Knockout mice for IL-13 show a significant reduction in Th2 cytokine production due to impairment in Th2 development. These mice do not develop airway hyperreactivity (AHR) in spite of the presence of eosinophil inflammation. The AHR was restored by administration of IL-13, indicating that IL-13 is necessary and sufficient for the induction of AHR in mouse. Other important biological functions of IL-13 in relationship with asthma include the induction of goblet cell metaplasia and mucus production. It acts directly on airway epithelial cells, fibroblasts and airway smooth muscle cells and induces different transcriptional programs in each of this cell types. Interestingly, IL-13 decreases the alpha-adrenergic response in smooth muscle cells, contributing to airway narrowing. IL-13 promoter polymorphism is associated with increased risk of allergic asthma. Polymorphisms in the IL-13 gene are associated with high serum IgE levels. Single nucleotide polymorphism in the intergene sequence between the IL-4 and IL-13 genes is associated with atopic asthma.
IL-13 antagonists have been utilized in animal models. For example a soluble mouse IL-13Rα2-IgGFc fusion protein has been used to show efficacy in completely reversing ovalbumin-induced AHR and the number of mucus containing cells. The reversal was obtained even if the treatment is given after full development of the phenotype. In addition, treatment of mice with an IL-13 fusion cytotoxin molecule resulted in reduction of all features of airway disease in a chronic fungal-induced allergic inflammation. In conclusion, IL-13 is a critical mediator of the effector arm of the allergic response.
IL-113Rα1 is a member of the hemapoietin receptor superfamily (type 1 cytokine receptor family) and identified and described by Obiri N. I., et al., J. Biol. Chem., 270 (1995) 8797-8804) and WO 96/29417. It is a protein of 427 amino acids including the signal sequence. Its DNA and protein sequences are described in WO 97/15663 and SwissProt No. P78552. IL-13Rα1 is a glycosylated protein binding to IL-13 with low affinity, but, when linked with IL-4Rα to a heterodimer, it binds IL-13 with high affinity. This complex is also a receptor for IL-4.
Antibodies against IL-13Rα1 are known from WO 96/29417, WO 97/15663, WO 03/080675, Graber P., et al., Eur. J. Immunol., 28 (1998) 4286-4298; Poudrier J., et al., J. Immunol., 163 (1999) 1153-1161; Poudrier J., et al., Eur. J. Immunol., 30 (2000) 3157-3164; Aikawa M., et al., Cytokine, 13 (2001) 75-84. Antibodies against IL-13Rα1 are commercially available from R&D Systems Inc. USA.